Ovulation induction simplified - gynaec perspective

infertility

1. OVULATION INDUCTION SIMPLIFIED Dr. Aarthy Sumaldha.S.P ., MS( Og ), DGO, D.N.B( Og ).,DRM VFRC

2. Focus of discussion Definition Basics of physiology pertaining to OI Drugs available Protocols used OI in various situations PCOS Hypo Hypo Unexplained infertility VFRC

3. Indications Unexplained infertility Ovulatory factor infertility Endometriosis related infertility Mild male factor subfertility Cervical factor infertility Donor sperm VFRC

4. Ovulation induction and COS Development of a follicle in an anovulatory patient-ovulation induction - Monofolliculogenesis Enhanced follicular development in an already ovulating patient-Controlled Ovarian Stimulation (COS) Multifolliculogenesis VFRC

5. Aim of Stimulation Protocols in IUI Recruiting multiple follicles Control timing of ovulation Adequate endometrial development Prevention of premature LH surge Cost effective and safe Optimal pregnancy rate Sinha SP. Apollo Medicine 2012. 9(3): 228-238 Controlled ovarian stimulation (COS), In IUI is to get 1-3 follicles In IVF cycles is to get 6-12 follicles

6. CC AI VFRC

7. WHO classification of ovulatory disorders Group I – Hypothalamic pituitary failure ( hypogonadotropic hypogonadism ) – 10% Group II – Hypothalamic pituitary dysfunction ( PCOS ) – 85% Group III – Ovulatory failure : Hypergonadotropic Hypogonadism – 4-5 % Turner’s, Autoimmune, Mumps, RT, CT VFRC

8. We need to individualize treatment Age, Race BMI Genetic profile Cause Duration Health Nutrition VFRC

9. Ideal stimulation 1 – 2 follicles Diameter 18 – 22 mm Endometrium >= 8 mm Triple line E2 >= 200 pg /ml Doppler : Perifollicular blood flow > 75% Monitoring – TVS Prevent complications – OHSS, HOMP VFRC

10. Drugs Available SERM - Clomiphene Citrate - Tamoxifene Aromatase Inhibitor - Letrozole - Anastrazole Gonadotropins VFRC

11. Clomiphene citrate First line treatment for >55 yrs since 1967 Synthetic , non steroidal anti estrogen (SERM) Ovulation : 60-85% 20-30% pregnancy rates only achieved due to its antiestrogenic effect on cervical mucus and endometrium. VFRC

12. Depletion of ER in pituitary & hypothalamus due to prolonged stimulation Estrogen feedback loop gets interrupted FSH secretion increased leading to multiple follicle growth Hypothalamus Pituitary CC binds to ER & depletes receptor concentrations More smaller follicles are rescued Multiple follicles develop estrogen – ve feedback interrupted FSH stimulation continues 1 2 3 4 5 CC: Mechanism of action Casper RF, et al. J Clin Endocrinol Metab . 2006; 91: 760-771. VFRC

13. Induces ovulation CC pituitary/hypothalamus endometrium cervical mucus isomers Endometrial thickness < 5-6 mm Reduction in glandular density Decreased uterine blood flow during early luteal phase Change in quantity or quality of mucus Anti-Estrogenic effects contributing to reduced pregnancy rates Miscarriage rate of 26% CC : Anti-estrogenic effects Casper RF, et al. J Clin Endocrinol Metab . 2006; 91: 760-771. VFRC

14. 1 2 3 4 5 6 7 8 9 10 11 12 13 Start Day Ultrasound Menses Ultrasound How to use CC? CC Dose : 50 mg / day for 5 days VFRC

15. 50 mg/d No Pregnancy Suboptimal Endometrium (thickness x 7mm) Injectable Gonadotropins No Ovulation 150 mg/d No No Ovulation Ovulation Ovulation Ovulation 2 - 3 cycles with the same dose 100 mg/d Ovulation VFRC RCOG guidelines with ACOG recommendation is that CC can be used maximum for 12 months in lifetime, maximum for 6 months continuously.

16. CC Resistance & Failure CC Resistance : Failure to achieve ovulation after induction with 150mg of CC in 3 consecutive cycles. CC Failure : Failure to achieve pregnancy after ovulation Options CC + insulin sensitizers Aromatase inhibitor Gonadotropin Laparoscopic ovarian drilling VFRC

17. Adverse effects with CC Vasomotor flushes Mood swings Visual disturbances (reversible) Nausea Multiple gestation 8-10 % Minimal risk of increased rates of ovarian cancer in women exposed to more than 12 cycles VFRC

18. Tamoxifen Off label use as OI agent – not licensed 20-40 mg/day , D2-D6, max 60mg/day Ovulation rate 65-75% Pregnancy rate-30-35% Advantages : -No antiestrogenic action on endometrium -Improve bone density and lipid profile VFRC

19. Aromatase inhibitors Letrozole VFRC

20. Milestones 2001- Mitwally and Casper introduced letrozole as OI agent in CC resistant PCOS women 2008- Requena et al proposed its use in women with unexplained infertility and mild endometriosis 2011 October BANNED VFRC

21. Sharma S, et al. PLoS ONE. 2014; 9(10): e108219 Letrozole use does not increase risk of congenital anomalies in newborns - Wang R, et al. BMJ. 2017; 356: j138. Tatsumi T, et al. Hum Reprod . 2017 Jan;32(1):125-132.

22. VFRC Ban on letrozole lifted after 5 long years Finally …… Legacy reborn

23. Hypothalamus Pituitary - ve feedback stimulation Smaller follicles undergo atresia Single follicle develop estrogen –ve feedback FSH stimulation 1 2 3 4 6 androstenedione  estrogen aromatase inhibition GnRH released Falling FSH 5 Letrozole : Mechanism of action Casper RF, et al. J Clin Endocrinol Metab . 2006; 91: 760-771. VFRC

24. Letrozole Shorter duration of action, half life of 45 hours More monofollicular response In PCOS patients, ovulation occurred in 75% and pregnancy was achieved in 25% No adverse antiestrogenic effects on the endometrium Dosage : 2.5 – 5 mg/day for 5 days VFRC

25. Extended protocol for CC-resistant PCOS women Dose: 2.5 mg of letrozole daily starting from day 1 of the menses for 10 days Daily fixed dose protocol for Superovulation and IUI Dose: 5 mg of letrozole daily from day 3-7 of menstrual cycle Step up protocol for Assisted reproduction Dose: 1, 2, 3, and 4 tablets of letrozole 2.5 mg daily on cycle days 2, 3, 4, and 5, respectively VFRC

26. Advantages of letrozole over CC Parameters Clomiphene citrate Letrozole MOA SERM Aromatase inhibitor Half-life Long, 5-7 days Short, 45 h Anti-estrogenic effects Thin e ndometrium & altered cervical mucus Thick endometrium & favourable cervical mucus Uterine blood flow Decreased Increased Miscarriages Possibly high Less incidence OHSS risk High Low Multiple pregnancy High Low 26 Casper RF, et al. J Clin Endocrinol Metab . 2006; 91: 760-771. American College of Obstetricians and Gynaecologists 2016 LTZ should be considered as 1 st -line therapy for OI in patients with PCOS & BMI > 30 because of increased LBR compared to CC VFRC

27. Gonadotropin Second line agent Indication Hypogonadotropic hypogonadism CC resistance CC failure Unexplained Mild/Minimal endometriosis Super ovulation combined with IUI COH in ART cycles VFRC

28. Gonadotropins VFRC

29. Clinical benefits of rFSH Greater purity and specific activity Smaller dose required More predictable response Reduced batch to batch variability No risk of contamination with drugs or metabolites Subcutaneous administration VFRC

30. Dose of Gonadotropin Age Weight of patient Level of basal FSH on D3 , AMH Previous response to similar therapy Other conditions like chronic PID , endometriosis VFRC

31. OI Step up Step down Sequential Conventional Chronic Low dose VFRC Low dose

32. Conventional Protocol 75-150IU/day starting from D2 or D3 daily until ovarian response occurs It is effective but is associated with - OHSS - Multiple Pregnancy VFRC

33. Rationale of the low dose regimens Very narrow therapeutic range of FSH Difference in the dose that causes growth and OHSS is very small Initiation of follicular growth requires only 10-30 % of increase in the dose of exogenous FSH VFRC

34. Starting dose Scan D7 Scan D14 hCG 5000 IU Lead follicle ≥ 18mm 50 – 75 IU /day Increase dose by 50% if needed; DF <10 mm Increase dose by 50% VFRC Low dose step up protocol

35. Starting dose Scan D7 Scan D14 hCG 5000 IU Lead follicle ≥ 18mm 37.5 – 75 IU /day Increase dose by 50% if needed; DF <10 mm Increase dose by 50% Scan D 21 90% of patients are ready by day 14 VFRC Chronic low dose protocol

36. Starting dose hCG 5000 IU Lead follicle ≥ 18mm Decrease by 37.5 IU Decrease by 37.5 IU 150 IU /day Follicle growing well Scan D8 Follicle > 9mm Scan D 4-5 VFRC Step down protocol

37. Step up protocol = Threshold concept Step down protocol = Window concept VFRC

38. Antagonist Protocol for IUI 50-100 mg CC / day 150 iu hMG /150 iu rec FSH 0.25 mg antagonist/day Follicle 14mm + 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 5000iu hCG Follicle 18mm

39. Monitoring of OI Baseline USG (D2/D3) to rule out residual cyst Start follicular tracking from D-10 in case of oral ovulogen With gonadotropin cycle TVS monitoring is done according to the protocol started Injection until dominant follicle reaches 18-19 m Study of endometrial blood flow, layering and thickness hCG at a dose of 5000-10,000 IU to trigger ovulation VFRC

40. OI in PCOS (WHO – II) VFRC

41. OI in Hypo Hypo (WHO – 1) VFRC

42. OI in Unexplained infertility VFRC

43. Take Home Message Reach a diagnosis FSH threshold and window concept form the backbone of OI/COS Oral ovulogens first wherever applicable 3-6 cycles of CC/LTZ – then switch over to gonadotropin Different gonadotropin products are equally effective Minimal required dosage VFRC

44. Take Home Message OI protocol must be tailor made to suit clinical condition of each patient Monitor for ovulation LPS should be added in gonadotropin OI and when >1 F grows Strict cancellation criteria to avoid MFG and OHSS With letrozole being 1 st line agent, CC role can become obsolete and the letrozole resistance can become a subject of debate VFRC

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